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Hondón de las Nieves, Spain

Miles D.,Mount Vernon Cancer Center | Roche H.,Institute Claudius Regaud | Martin M.,Oncology Service | Perren T.J.,University of Leeds | And 8 more authors.
Oncologist | Year: 2011

Purpose. This double-blind, randomized, phase III clinical trial evaluated time to progression (TTP) and overall survival in women with metastatic breast cancer (MBC) who received sialyl-TN (STn) keyhole limpet hemocyanin (KLH) vaccine. Secondary endpoints included vaccine safety and immune response. Experimental design. The study population consisted of 1,028 women with MBC across 126 centers who had previously received chemotherapy and had had either a complete or a partial response or no disease progression. All women received one-time i.v. cyclophosphamide (300 mg/m 2) 3 days before s.c. injection of 100 μg STn-KLH plus adjuvant (treatment group) or 100 μg KLH plus adjuvant (control group) at weeks 0, 2, 5, and 9. Subsequently, STn-KLH without adjuvant or KLH without adjuvant was then administered monthly for 4 months, and then quarterly until disease progression, without cyclophosphamide. Results. STn-KLH vaccine was well tolerated; patients had mild to moderate injection-site reactions and reversible flu-like symptoms. Week-12 antibody testing revealed high specific IgG titers and a high rate of IgMto- IgG seroconversion; the median IgG titers in STn- KLH recipients were 320 (anti-ovine submaxillarymucin) and 20,480 (anti-STn), with no detectable antimucin antibodies in the control group. The TTP was 3.4 months in the treatment group and 3.0 months in the control group. The median survival times were 23.1 months and 22.3 months, respectively. Conclusions. Although STn-KLH was well tolerated in this largest to date metastatic breast cancer vaccine trial, no overall benefit in TTP or survival was observed. Lessons were learned for future vaccine study designs. © AlphaMed Press.

Fernandez O.,Oncology Service | Afonso J.,University of La Coruna | Vazquez S.,Lucus Augustis University Hospital | Campos B.,Lucus Augustis University Hospital | And 3 more authors.
Anti-Cancer Drugs | Year: 2014

Docetaxel is the standard first-line chemotherapy for men with metastatic castration-resistant prostate cancer. Until recently, there was no standard therapy after failure of docetaxel treatment. Cabazitaxel has been shown to improve overall survival in this setting. As a result, the treatment paradigm for mCRPC is changing rapidly. The improved survival shown with cabazitaxel provides an important new opportunity to treat men with mCRPC after docetaxel treatment. Despite the toxicity recorded in the pivotal study, subsequent trials have shown that cabazitaxel is a safe drug. Patient selection and the optimal interval between prior docetaxel treatment and cabazitaxel remain the critical issues. According to a subanalysis of the various studies discussed in this review, there is a patient profile that will probably benefit from use of cabazitaxel after docetaxel failure. Cabazitaxel represents a new treatment option for patients with prostate cancer. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Casal C.,University of Granada | Torres-Collado A.X.,University of Barcelona | Plaza-Calonge M.D.C.,University of Granada | Martino-Echarri E.,University of Granada | And 4 more authors.
Cancer Research | Year: 2010

Cancer stem cells have been hypothesized to explain tumor plasticity, including the capability to adopt distinct differentiation commitments. Among the mechanisms of tumor neovascularization, the ability of some malignant cells to mimic an endothelial phenotype has been recognized by a capacity to form matrix-enriched pseudovascular structures. In addition to the expression of genes associated with an endothelial nature, the molecular dynamism of specific microenvironments may also be critical. Here, we report the identification of the extracellular protease ADAMTS1 as a critical molecule for tumor cells to acquire endothelial-like properties. In a fibrosarcoma model, ADAMTS1 increased tumor growth rate in an angiogenesis-independent manner, influencing the tumor cells to display an exclusive endothelial-like gene signature. We documented the relevant expression of ADAMTS1 in aggressive and highly plastic melanoma and Ewing sarcoma cells. Notably, inhibiting ADAMTS1 action compromised the endothelial mimetic attributes observed in this setting. Our findings provide insights into how the tumor microenvironment can elicit endothelial mimicry by tumor cells. ©2010 AACR.

Ulla-Rocha J.L.,Digestive Disease Service | Vilar-Cao Z.,Family Medicine | Alvarez-Martinez M.,Anatomical Pathology | Salgado-Boquete L.,Oncology Service
Journal of Gastrointestinal Cancer | Year: 2012

Background: After treatment intended to cure systemic neoplasms, a series of monitoring strategies are followed. Objective To analyse our experience in confirming the cases of lymphatic or extraparietal relapse in areas accessible to endoscopic ultrasonography plus fine-needle aspiration (EUS-FNA) in long-term monitoring (>1 year of treatment for the primary neoplasm) and define what implications have been derived with regards histopathological confirmation in relation to treatment. Materials and Methods: Retrospective analysis was made of all EUS-FNA carried out in our Endoscopy Unit during the period from 1/07/2007 to 28/02/2010 by means of searches in the Endobase (Olympus) database. Medical records of patients and drug therapy were reviewed in order to check the chemotherapy used in each case. Results: From a total of 154 EUS-FNA carried out in our service, we have detected histopathological confirmation of malignancy in primary neoplasm treated with initial curative intention at least 1 year before. Locations were: esophageal extraparietal involvement of a squamous cell carcinoma (one patient), perirectal adenopathy of rectal adenocarcinoma (one patient), multiple lymphatic relapse of melanoma (two patients), perigastric adenopathy relapse of gastric adenocarcinoma (one patient), pancreatic head mass secondary to initial breast ductal carcinoma (one patient). In all cases, this fact has involved a directed treatment: surgery (one patient), radiotherapy (one patient), chemotherapy (four patients). Conclusions: Confirmation by means of EUS-FNA of late relapse in any section of the digestive tract allowed a treatment to be carried out by surgery, radiotherapy, or chemotherapy. © Springer Science+Business Media, LLC 2010.

Borras E.,Molecular Genetics Unit | Jurado I.,Pathology Service | Hernan I.,Molecular Genetics Unit | Gamundi M.J.,Molecular Genetics Unit | And 7 more authors.
BMC Cancer | Year: 2011

Background: Epidermal growth factor receptor (EGFR) and its downstream factors KRAS and BRAF are mutated in several types of cancer, affecting the clinical response to EGFR inhibitors. Mutations in the EGFR kinase domain predict sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in lung adenocarcinoma, while activating point mutations in KRAS and BRAF confer resistance to the anti-EGFR monoclonal antibody cetuximab in colorectal cancer. The development of new generation methods for systematic mutation screening of these genes will allow more appropriate therapeutic choices.Methods: We describe a high resolution melting (HRM) assay for mutation detection in EGFR exons 19-21, KRAS codon 12/13 and BRAF V600 using formalin-fixed paraffin-embedded samples. Somatic variation of KRAS exon 2 was also analysed by massively parallel pyrosequencing of amplicons with the GS Junior 454 platform.Results: We tested 120 routine diagnostic specimens from patients with colorectal or lung cancer. Mutations in KRAS, BRAF and EGFR were observed in 41.9%, 13.0% and 11.1% of the overall samples, respectively, being mutually exclusive. For KRAS, six types of substitutions were detected (17 G12D, 9 G13D, 7 G12C, 2 G12A, 2 G12V, 2 G12S), while V600E accounted for all the BRAF activating mutations. Regarding EGFR, two cases showed exon 19 deletions (delE746-A750 and delE746-T751insA) and another two substitutions in exon 21 (one showed L858R with the resistance mutation T590M in exon 20, and the other had P848L mutation). Consistent with earlier reports, our results show that KRAS and BRAF mutation frequencies in colorectal cancer were 44.3% and 13.0%, respectively, while EGFR mutations were detected in 11.1% of the lung cancer specimens. Ultra-deep amplicon pyrosequencing successfully validated the HRM results and allowed detection and quantitation of KRAS somatic mutations.Conclusions: HRM is a rapid and sensitive method for moderate-throughput cost-effective screening of oncogene mutations in clinical samples. Rather than Sanger sequence validation, next-generation sequencing technology results in more accurate quantitative results in somatic variation and can be achieved at a higher throughput scale. © 2011 Borràs et al; licensee BioMed Central Ltd.

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